ABSTRACT
A series of analogs of the immunomodulary drugs lenalidomide (1) and pomalidomide (2), in which the amino group is replaced with various isosteres, was prepared and assayed for immunomodulatory activity and activity against cancer cell lines. The 4-methyl and 4-chloro analogs 4 and 15, respectively, displayed potent inhibition of tumor necrosis factor-α (TNF-α) in LPS-stimulated hPBMC, potent stimulation of IL-2 in a human T cell co-stimulation assay, and anti-proliferative activity against the Namalwa lymphoma cell line. Both of these analogs displayed oral bioavailability in rat.
Subject(s)
Thalidomide/analogs & derivatives , Administration, Oral , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Half-Life , Humans , Interleukin-2/metabolism , Lenalidomide , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Rats , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Thalidomide/chemistry , Thalidomide/pharmacokinetics , Thalidomide/toxicity , Tumor Necrosis Factor-alpha/metabolismABSTRACT
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.
Subject(s)
2-Aminopurine/chemistry , 2-Aminopurine/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Purines/chemistry , Reperfusion Injury/enzymology , Animals , Catalytic Domain , Dogs , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haplorhini , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Purines/pharmacology , Rats , Reperfusion Injury/drug therapy , Structure-Activity RelationshipABSTRACT
In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.
Subject(s)
Cyclohexanols/chemistry , Cyclohexanols/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , MAP Kinase Kinase 4/antagonists & inhibitors , Purines/chemistry , Purines/pharmacology , Administration, Oral , Animals , Catalytic Domain , Cyclohexanols/administration & dosage , Dogs , Enzyme Activation/drug effects , Enzyme Inhibitors/administration & dosage , Haplorhini , Idiopathic Pulmonary Fibrosis/drug therapy , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Purines/administration & dosage , Rats , Structure-Activity RelationshipABSTRACT
In this communication, we report the discovery of 1S (apremilast), a novel potent and orally active phosphodiesterase 4 (PDE4) and tumor necrosis factor-alpha inhibitor. The optimization of previously reported 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-(3,4-dimethoxyphenyl)propionic acid PDE4 inhibitors led to this series of sulfone analogues. Evaluation of the structure-activity relationship of substitutions on the phthalimide group led to the discovery of an acetylamino analogue 1S, which is currently in clinical trials.
Subject(s)
Drug Discovery , Phosphodiesterase 4 Inhibitors , Phosphodiesterase Inhibitors/pharmacology , Thalidomide/analogs & derivatives , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Administration, Oral , Animals , Humans , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Thalidomide/administration & dosage , Thalidomide/chemistry , Thalidomide/pharmacologyABSTRACT
Our policy of conducting biotransformation studies with extended chromatography prior to pharmacokinetic bioanalyses allowed us to quickly detect an unusual, cis/trans metabolite in rat plasma that was inseparable using a short chromatographic method. We caution investigators that short methods invite unknown isobaric metabolites to cause inaccuracies in plasma concentration measurements.
Subject(s)
Chromatography, Liquid/methods , Cyclohexanols/metabolism , Pharmaceutical Preparations/metabolism , Animals , Biotransformation , Drug Discovery/methods , Female , Hepatocytes/metabolism , Male , Rats , Rats, Sprague-Dawley , StereoisomerismABSTRACT
We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC(50) value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G(2)-M phase, increased phosphorylation of G(2)-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [(3)H]colchicine for binding to tubulin; however, it does not compete with [(3)H]paclitaxel (Taxol) or [(3)H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor-alpha (TNF-alpha) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC(50), 270 nmol/L). This inhibitory effect on TNF-alpha production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy.
Subject(s)
Nitriles/pharmacology , Tubulin/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Animals , Cell Cycle/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Mice , Neoplasms/pathology , Transplantation, Heterologous , Tubulin Modulators/pharmacology , Tumor Cells, CulturedABSTRACT
The thalidomide analogue and immunomodulatory drug (IMiD) lenalidomide (CC-5013, REVLIMID) is emerging as a useful treatment for a number of cancers and has recently entered phase III trials for multiple myeloma. It has been suggested that the anti-tumor effect of lenalidomide is related to its anti-angiogenic potency. In this regard, we have previously shown that lenalidomide inhibits angiogenesis in both rat and human in vitro models but does not affect endothelial cell proliferation. We now show that oral administration of lenalidomide attenuates growth factor-induced angiogenesis in vivo; the rat mesenteric window assay was utilized to show that lenalidomide significantly inhibits vascularization in a dose-dependent manner. We also found that lenalidomide significantly inhibits growth factor-induced endothelial cell migration. This correlates with the inhibitory effect of lenalidomide on growth factor-induced Akt phosphorylation, thereby providing a potential mechanism for its anti-migratory and subsequent anti-angiogenic effects. These data further support the use of lenalidomide as an orally administered drug for the effective treatment of angiogenesis-dependent conditions, including cancer, and suggest a potential mechanism of action.
